The most common cause of inherited blindness is retinitis pigmentosa, a family of diseases with various forms of inheritance caused by mutations in more than 45 genes. The rhodopsin gene has more than 100 distinct mutations, and many forms of autosomal dominant retinitis pigmentosa (adRP) involve abnormal rhodopsin folding in which the misfolded protein is retained in the endoplasmic reticulum. However, it is not known how misfolded rhodopsin leads to the photoreceptor degeneration seen in the disease. The unfolded protein response (UPR) comprises a set of cellular signaling pathways present in all mammalian cells that detects misfolded proteins in the endoplasmic reticulum and directs protective and apoptotic actions taken by the cell. UPR signaling acts cytoprotectively by elevating chaperone levels;elevating ubiquitin-proteasome system activity;and reducing protein translation, all of which cumulatively decrease misfolded protein levels. UPR signaling can also trigger apoptosis through mitochondrial-dependent cytochrome C release and downstream activation of caspase-dependent protease cascades. This proposal investigates the role of UPR signaling in the pathogenesis of adRP using tissue culture systems and transgenic animal models of P23H-rhodopsin adRP. Specifically, this project aims to: 1) Determine the mechanism by which the photoreceptor senses misfolded rhodopsin, 2) Determine how rhodopsin misfolding lead to apoptosis, and 3) Test if modulation of the UPR can prevent misfolded rhodopsin-induced cell death. Dr. Jonathan Lin, the principal investigator, is an M.D., Ph.D., who received his graduate degree in neuroscience, completed his residency training in anatomic pathology, and wishes to develop the skills necessary to become an independent physician-scientist. The sponsor, Dr. Peter Walter, discovered the Unfolded Protein Response and has a strong record of training successful physician-scientist investigators. The co-sponsor, Dr. Matthew LaVail, is an expert in vision biology and retinal degeneration, and created and characterized the P23H-rhodopsin transgenic rat models of adRP.